In recent years, many investigators have shown interest in the method of synthesis and biological activity of bisphosphonates and their derivatives, which can be regarded as analogues of natural pyrophosphates. Pyrophosphates are known to be natural regulators of Ca2+ metabolism at the cellular level and form many nucleotides. Synthetic analogues of pyrophosphates, namely bisphosphonates, are not metabolized because their P—C—P bonds are less labile than the P—O—P linkage of natural pyrophosphates.
The elucidation and further development of structure-activity relationships in the bisphosphonate class of compounds has increasingly flourished during the past few years, as recently reviewed by Ebetino(1). Rational design of new medicinal agents based on bisphosphonates has progressed from simple α-alkyl and α-halo bisphosphonates, to bisphosphonates substituted with a range of heterocyclic and heteroatomic moieties. Bisphosphonate chemistry has yielded an increasing variety of bone-active compounds, including potent antiresorptive agents that have therapeutic potential in osteoporosis and other diseases of bone metabolism. Variation in the P—C—P backbone has led to analogues of varied hydroxyapatite affinity, Ca2+ chelation and antimineralization properties.
Current theory attributes the biological activity of anti-resorptive bisphosphonates to two design components. One of these is the so-called ‘bone hook’ functionality, associated with the bisphosphonate backbone, e.g., in [(HO)2P(O)CR(OH)P(O)(OH)2], all of the molecule except the “R” substituent. This functionality is directly responsible for primary hydroxyapatite adsorption. A second “bioactive” moiety is postulated to modulate the anti-resorptive potency of the drug within a given affinity class.
It should be noted that α-hydroxy bisphosphonates possess high affinity for hydroxyapatite and include some of the most potent antiresorptive agents, thus chemistry that generates an α-hydroxy function together with addition of the R group is particularly desirable. Indeed the compound hydroxyethylidenediphosphonic acid (HEDP) (HO)2P(O)CCH3(OH)P(O)(OH)2, where R=CH3 is one of the best known bisphosphonates used in medicine under the name Etidronate (disodium salt of HEDP). HEDP is a useful complexing agent for alkaline earth, transition, and lanthanide metals, can be used to regulate calcium metabolism in the treatment of Paget's disease, inhibits formation and growth of calcium oxalate stones in kidneys, can reduce plaque when added to dental preparations, and has been indicated for treatment of diseases ranging from bone cancer to osteoporosis and arthritis.
Design and synthesis of new bisphosphonate containing drugs active against bone diseases would be greatly aided by preparative methodology facilitating introduction of the “R” moiety into the bisphosphonate structure. Such methodology, should it be available, could also be employed for preparation of bisphosphonates that might be useful in treating many other diseases, such as viral infections, or other health disorders that may be responsive to phosphonate drugs.
One such useful modification might include modified nucleosides, which have acquired an important role as therapeutic agents in the treatment of diseases caused by infectious viruses such as human immunodeficiency virus (HIV), or herpes viruses (2,3). Despite the advent of potent new antiviral nucleoside analogues such as carbovir (4) and abacavir (5,6), AZT (3′-azido-3′-deoxythymidine) continues to play an important role in the chemotherapy of AIDS (7-9), particularly in combination with other HIV reverse transcriptase (RT) nucleoside analogue inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and HIV protease inhibitors (10-11).
α,β-methylene analogues of nucleoside diphosphates (12-15) or β,γ-methylene analogues of nucleoside triphosphates (4, 16-19) have been previously studied. Replacement of the anhydride oxygen by the less electronegative carbon atom increases the P—OH pKa values; however this can be addressed by fluorine substitution (20). Replacement of the anhydride oxygen by a reactive carbon group, which is also sterically minimal and electronegative, represents a more challenging problem.